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  • 1.
    Arnaudeau, Catherine
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Lundin, Cecilia
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutionen för tillämpad kommunikationsvetenskap - GI och IHR.
    Helleday, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    DNA Double-strand Breaks Associated with Replication Forks are Predominantly Repaired by Homologous Recombination Involving an Exchange Mechanism in Mammalian Cells2001Inngår i: Journal of Molecular Biology, ISSN 0022-2836, Vol. 307, nr 5, s. 1235-45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    DNA double-strand breaks (DSB) represent a major disruption in the integrity of the genome. DSB can be generated when a replication fork encounters a DNA lesion. Recombinational repair is known to resolve such replication fork-associated DSB, but the molecular mechanism of this repair process is poorly understood in mammalian cells. In the present study, we investigated the molecular mechanism by which recombination resolves camptothecin (CPT)-induced DSB at DNA replication forks. The frequency of homologous recombination (HR) was measured using V79/SPD8 cells which contain a duplication in the endogenous hprt gene that is resolved by HR. We demonstrate that DSB associated with replication forks induce HR at the hprt gene in early S phase. Further analysis revealed that these HR events involve an exchange mechanism. Both the irs1SF and V3-3 cell lines, which are deficient in HR and non-homologous end joining (NHEJ), respectively, were found to be more sensitive than wild-type cells to DSB associated with replication forks. The irs1SF cell line was more sensitive in this respect than V3-3 cells, an observation consistent with the hypothesis that DSB associated with replication forks are repaired primarily by HR. The frequency of formation of DSB associated with replication forks was not affected in HR and NHEJ deficient cells, indicating that the loss of repair, rather than the formation of DSB associated with replication forks is responsible for the increased sensitivity of the mutant strains. We propose that the presence of DSB associated with replication forks rapidly induces HR via an exchange mechanism and that HR plays a more prominent role in the repair of such DSB than does NHEJ

  • 2. Hansen, Lasse Tengbjerg
    et al.
    Lundin, Cecilia
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutionen för tillämpad kommunikationsvetenskap - GI och IHR.
    Spang-Thomsen, Mogens
    Petersen, Lone Norgård
    Helleday, Thomas
    The Role of RAD51 in Etoposide (VP16) Resistance in Small Cell Lung Cancer2003Inngår i: International Journal of Cancer, ISSN 0020-7136, Vol. 105, nr 4, s. 472-9Artikkel i tidsskrift (Fagfellevurdert)
  • 3.
    Lundin, Cecilia
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutionen för tillämpad kommunikationsvetenskap - GI och IHR.
    Homologous recombination at replication forks in mammalian cells2004Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Accumulating evidence indicates that homologous recombination plays an important role in mammalian cells, primarily in the reactivation of stalled replication forks. During a normal round of replication, stalling of the replication fork occurs frequently when a nick or a lesion, which cannot be by-passed, is encountered. Progression of the replication fork can also be hindered by a protein bound to or secondary structures in the DNA. It is vital for the cell to restart stalled replication forks efficiently since nucleases might otherwise damage the unprotected DNA and since failure to reinitiate replication leads ultimately to cell death. The mechanism by which homologous recombination reactivates stalled replication forks and the substrates that trigger this response in mammalian cells have not yet been elucidated.

    The present thesis focuses on the function of homologous recombination as well as on the mechanism for induction of this process in mammalian cells. Our major interest in this context was the repair of lesions encountered during replication and that interfere with replication fork progression. The role of the RAD51 protein in this process was also examined. The main experimental system we employed consisted of Chinese hamster cell lines deficient in different DNA repair pathways, as well as the V79 Chinese hamster SPD8 cell line, which contains an endogenous locus at which homologous recombination events can be monitored.

    Our findings demonstrate that homologous recombination can be employed by mammalian cells to repair several different types of lesions encountered during replication. The mechanism underlying such homologous recombinational repair appears to depend on the type of lesion involved. A replication fork encountering a single-strand break was shown to collapse into a double-strand break and subsequently be repaired by homologous recombination involving a mechanism referred to as break-induced replication. A stalled replication fork was shown to induce a substrate for homologous recombination both with and without the induction of a double-strand break. This suggests that homologous recombination could repair lesions other than double-strand breaks during replication. Non-homologous end-joining was shown to play only a minor role in the repair of DNA damage associated with replication, being employed only in situations when the replication fork is processed into a double-strand break.

    Experiments concerning the role of RAD51 in repair of lesions encountered during replication, employing a cell line that overexpresses this protein, indicated that RAD51 is rate limiting for the repair of DNA damage associated with the replication fork. The level of RAD51 was also measured in lung cancer cells and found to determine both the survival and the level of double-strand breaks formed in response to etoposide treatment, suggesting RAD51 to be involved in the resistance of tumours to chemotherapeutic drugs.

    In summary, our findings demonstrate that RAD51-dependent homologous recombination is an important repair pathway during replication in mammalian cells.

  • 4.
    Lundin, Cecilia
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutionen för tillämpad kommunikationsvetenskap - GI och IHR.
    Johansson, Fredrik
    Erixon, Klaus
    Helleday, Thomas
    Alkylating DNA Lesions Associated with Replication are Repaired by Homologous Recombination in Mammalian CellsManuskript (Annet vitenskapelig)
  • 5.
    Lundin, Cecilia
    et al.
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutionen för tillämpad kommunikationsvetenskap - GI och IHR.
    Schultz, Niklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Arnaudeau, Catherine
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Mohindra, Atul
    2The Institute for Cancer Studies, University of Sheffield.
    Hansen, Lasse Tengbjerg
    3Institute of Molecular Pathology, University of Copenhagen.
    Helleday, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    RAD51 is Involved in Repair of Damage Associated with DNA Replication in Mammalian Cells2003Inngår i: Journal of Molecular Biology, ISSN 0022-2836, Vol. 328, nr 3, s. 521-35Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The RAD51 protein, a eukaryotic homologue of the Escherichia coli RecA protein, plays an important role in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) in mammalian cells. Recent findings suggest that HR may be important in repair following replication arrest in mammalian cells. Here, we have investigated the role of RAD51 in the repair of different types of damage induced during DNA replication with etoposide, hydroxyurea or thymidine. We show that etoposide induces DSBs at newly replicated DNA more frequently than γ-rays, and that these DSBs are different from those induced by hydroxyurea. No DSB was found following treatment with thymidine. Although these compounds appear to induce different DNA lesions during DNA replication, we show that a cell line overexpressing RAD51 is resistant to all of them, indicating that RAD51 is involved in repair of a wide range of DNA lesions during DNA replication. We observe fewer etoposide-induced DSBs in RAD51-overexpressing cells and that HR repair of etoposide-induced DSBs is faster. Finally, we show that induced long-tract HR in the hprt gene is suppressed in RAD51-overexpressing cells, although global HR appears not to be suppressed. This suggests that overexpression of RAD51 prevents long-tract HR occurring during DNA replication. We discuss our results in light of recent models suggested for HR at stalled replication forks.

  • 6.
    Noaksson, Erik
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Institutionen för tillämpad kommunikationsvetenskap - GI och IHR.
    Environmental Monitoring of Refuse Dump Leachate Toxicity in Fish2003Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The global economy is driven by the consumption of goods and materials. Used products are often deposited on refuse dumps, making them potential point sources for all man-made chemicals. Water soaking through landfill waste results in a wastewater termed leachate. The collection and treatment of leachate is generally inadequate, but leachate toxicity is a surprisingly neglected area of research. This thesis covers six consecutive years (1996-2001) of environmental monitoring of toxicological effects and reproductive status in perch (Perca fluviatilis) from two Swedish lakes: Lake Molnbyggen, located within the same drainage area as a municipal refuse dump at Lindbodarna, and the reference Lake Djursjön. Toxicological and reproductive effects have been monitored also in fish from several other leachate-contaminated waters, including the stream Vadbäcken which drains the dump area and empties into Molnbyggen, and Lake Siljan, a recipient for the sewage treatment plant (STP) which processes some of the leachate from Lindbodarna. Unusually high frequencies of fin erosion and unique open body sores were found on Molnbyggen perch in 1996. They also had increased hepatic activities of catalase and glutathione-S-transferase. A weak induction of ethoxyresorufin O-deethylase (EROD) and low levels of DNA adducts indicated that the undersized gonads, observed in both sexes, were caused by pollutants specifically targeting gametogenesis. Later samplings revealed exceptionally low ratios of sexually mature (SM) females among both perch from Molnbyggen and brook trout (Salvelinus fontinalis) from Vadbäcken. Together with low gonadosomatic index (GSI), low brain aromatase (P450arom) activity, and low circulating levels of testosterone (T) and 17β-estradiol (E2) in both species, these results suggested a similar exposure to endocrine disrupting substances (EDSs) present in the refuse dump leachate. It was hypothesised that the aromatase activity could be inhibited by these EDSs, thereby disturbing the conversion of androgens into estrogens. An analysis of progesterone and 17α-hydroxyprogesterone indicated, however, that the low T levels in female perch and brook trout could result from a disturbance in its synthesis and that the low aromatase activity most likely was a result of down-regulation at the mRNA and/or protein level rather than a result of inhibition. In vitro studies of aromatase inhibition by chemical extracts of Molnbyggen sediments supported this conclusion. Mechanistic studies covering a single reproductive cycle further demonstrated that the disturbed synthesis of androgens could be a possible mechanism behind the reproductive failures, since too low T levels might be insufficient to activate the reproductive axis in leachate-exposed females. Analysis of 17α,20β-dihydroxy-4-pregnen-3-one (17α,20β-P) showed for the first time that it is the maturation-inducing hormone in this species. Three out of the four additional leachate-contaminated lakes investigated had low ratios of SM female perch. In Lake Nedre Vättern, the low ratio of SM females was associated with the same open body sores as in Molnbyggen, low GSI, low levels of T and E2, and high EROD activity, suggesting that the effects found in Molnbyggen and Vadbäcken are not unique. In Siljan, however, the low ratios of SM female perch found outside the STP were not associated with endocrine disruption. The EDSs responsible for the reproductive failures and endocrine disruption still remain unknown, thus the results of this thesis imply that the inappropriate handling of leachate from Swedish refuse dumps constitutes a serious environmental problem with unforeseeable consequences for wildlife and future generations.

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